In recent years, as lifestyles have been westernized and the population has been aging, more and more people have suffered from atherosclerotic diseases such as myocardial infarction, angina pectoris, cerebral apoplexy and peripheral vascular diseases even in our country. As a reliable treatment for such atherosclerotic diseases, percutaneous transluminal angioplasty (hereinafter referred to as “PTA”), such as percutaneous transluminal coronary angioplasty for a coronary artery of a heart, which surgically dilates a stenosis or obstruction of a blood vessel, is widely used.
PTA is a manipulative technique in which a thin tube (balloon catheter) with a balloon at its end is passed through a stenosis within a blood vessel, then the balloon at the end is inflated to dilate the stenosed blood vessel, and thus normal blood flow is restored. By doing this, the lumen of the blood vessel in an affected area is dilated, and thus the blood flow through the lumen of the blood vessel is increased. In addition to atherosclerotic diseases, PTA is also used such as in a stenosis treatment for a shunt blood vessel formed in an arm of a hemodialysis patient.
In general, the portion of a blood vessel that has been subjected to PTA is damaged such as by the detachment of endothelial cells and the injury of elastic laminas, and a vascular intima grows as a healing reaction for a vascular wall, with the result that restenosis occurs in about 30 to 40% of the stenosed areas that have been successfully dilated by PTA.
More specifically, human restenosis is considered to result primarily from an inflammatory process that occurs one to three days after PTA due to the adhesion and invasion of monocytes and the intimal thickening formation process of smooth muscle cells which grow most rapidly about forty five days after PTA. Since, when restenosis occurs, it is necessary to perform PTA again, the establishment of prophylaxis and treatment thereof is urgently required.
To meet the requirement, attempts have been widely proposed to reduce the restenosis rate by using a drug-eluting device in which an anti-inflammatory drug or a smooth muscle cell growth inhibitor is carried on the surface of a stent or balloon catheter made of a metal or high-polymer material and thereby releasing the drug locally in a site of a lumen where the device is indwelt over a long period of time. For example, in patent documents 1 and 2, there are proposed drug-eluting catheters in which the expanding portion (balloon) of the catheter is polymer coated, and a therapeutic drug such as a nucleic acid drug is incorporated into the polymer coating.
Since restenosis results primarily from smooth muscle cell growth, it is determined that it is most effective to inhibit the growth of the smooth muscle cells during a time period from the date when the growth of the smooth muscle cells is found in an intimal as a pathological finding, that is, the date when 30 days elapse after the start of a treatment to the date when the cells grow most rapidly, that is, the date when 45 days elapse. Hence, it is considered that it is most effective to design a drug-eluting catheter such that the amount of drug released peaks at least both during a period of 10 days after the start in order to inhibit an inflammatory process and during a period of 30 to 60 days in order to inhibit the growth of the smooth muscle cells and that the drug necessary to indicate its efficacy is evenly released for each period.
However, since, in the methods of patent documents 1 and 2, the polymer layer is decomposed in vivo and then the drug is released, the drug is released insufficiently in the early stage of the indwelling of the catheter, and thus it is impossible to effectively inhibit an inflammatory process occurring during a period of 1 to 3 days after the catheter is indwelt. When a hydrogel polymer is used as in patent document 1, since a water-soluble drug such as a decoy oligonucleotide is eluted in a short period of time, it is not easy to control the rate at which the drug is released.
In patent document 3, there is disclosed a drug-eluting stent (hereinafter referred to as a “DES”) in which a first bioactive substance is contained in a polymer layer formed on the surface of the stent, and a biocompatible nano- or microcapsule entrapping a second bioactive substance is further contained, and thus it is possible to release the first bioactive substance in the early stage and then gradually release the second bioactive substance within the capsule. According to the method of patent document 3, a suspension of nanoparticles is sprayed or applied onto the main body of the stent or the main body of the stent is immersed in the suspension of nanoparticles, and thus the nanoparticles are adhered to the stent main body. However, with this type of method, it is difficult to uniformaly adhere a sufficient number of nanoparticles.
Here, the structure of a conventional biocompatible nanoparticle is shown in FIG. 19. The surface of the conventional biocompatible nanoparticle (hereinafter simply referred to as the “nanoparticle”) 1 is coated with polyvinyl alcohol 2; a bioactive substance 3 is entrapped therewithin; and, in general, the surface is negatively charged. However, since a cell membrane in vivo is negatively charged, an electrical repulsion force disadvantageously causes the nanoparticle as shown in FIG. 19 to be poorly adhered to cells. In order for the entrapped bioactive substance to be locally and effectively incorporated into a lesion such as a stenosis, it is necessary to further enhance the movement of the nanoparticles into the cells.
Moreover, since biocompatible polymers are generally hydrophobic (liposoluble) and thus liposoluble bioactive substances alone can be entrapped into nanoparticles with high probability, it is difficult to sufficiently coat, by the method of patent document 3, the surface of the stent with a hydrophilic (water-soluble) bioactive substance such as a nucleic acid or a gene.
To overcome this problem, in patent document 4, there is disclosed a DES in which biocompatible nanoparticles whose surface is positive-charge-modified are electrically adhered to the main body of the stent, and there is also disclosed a method of manufacturing a DES by adhering the nanoparticles to the stent main body in an electrical continuous state, using electrophoresis, ultrasonic mist or the like. In patent document 5, there is disclosed a medical device having nanocapsules (nanoparticles) composed of a therapeutic drug, a magnetic or paramagnetic material and a polyelectrolyte multilayer shell, and a catheter is described therein as an example of the medical device.
Patent document 1: JP-T-H09-500561
Patent document 2: JP-T-2003-521275
Patent document 3: JP-A-2004-357986
Patent document 4: JP-A-2007-215620
Patent document 5: JP-T-2006-518736